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Pathogen entry route can have a strong impact on the result of microbial infections in different hosts, including insects.  Drosophila melanogaster  has been a successful model system to study the immune response to systemic viral infection. Here we investigate the role of the Toll pathway in resistance to oral viral infection in  D. melanogaster . We show that several Toll pathway components, including Spätzle, Toll, Pelle and the NF-kB-like transcription factor Dorsal, are required to resist oral infection with  Drosophila  C virus. Furthermore, in the fat body Dorsal is translocated from the cytoplasm to the nucleus and a Toll pathway target gene reporter is upregulated in response to  Drosophila  C Virus infection. This pathway also mediates resistance to several other RNA viruses (Cricket paralysis virus, Flock House virus, and Nora virus). Compared with control, viral titres are highly increased in Toll pathway mutants. The role of the Toll pathway in resistance to viruses in  D. melanogaster  is restricted to oral infection since we do not observe a phenotype associated with systemic infection. We also show that  Wolbachia  and other  Drosophila -associated microbiota do not interact with the Toll pathway-mediated resistance to oral infection. We therefore identify the Toll pathway as a new general inducible pathway that mediates strong resistance to viruses with a route-specific role. These results contribute to a better understanding of viral oral infection resistance in insects, which is particularly relevant in the context of transmission of arboviruses by insect vectors.

The Toll-Dorsal Pathway Is Required for Resistance to Viral Oral Infection in Drosophila